12-101757335-A-G

Position:

• chr12-101757335-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024312.5(GNPTAB):​c.3336-25T>C variant causes a intron change. The variant allele was found at a frequency of 0.304 in 1,299,802 control chromosomes in the GnomAD database, including 61,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7344 hom., cov: 32)
  • Exomes 𝑓: 0.30 (53853 hom.)
• Consequence: GNPTAB NM_024312.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.01

Genes affected

GNPTAB (HGNC:29670): (N-acetylglucosamine-1-phosphate transferase subunits alpha and beta) This gene encodes two of three subunit types of the membrane-bound enzyme N-acetylglucosamine-1-phosphotransferase, a heterohexameric complex composed of two alpha, two beta, and two gamma subunits. The encoded protein is proteolytically cleaved at the Lys928-Asp929 bond to yield mature alpha and beta polypeptides while the gamma subunits are the product of a distinct gene (GeneID 84572). In the Golgi apparatus, the heterohexameric complex catalyzes the first step in the synthesis of mannose 6-phosphate recognition markers on certain oligosaccharides of newly synthesized lysosomal enzymes. These recognition markers are essential for appropriate trafficking of lysosomal enzymes. Mutations in this gene have been associated with both mucolipidosis II and mucolipidosis IIIA.[provided by RefSeq, May 2010]

GNPTAB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-101757335-A-G is Benign according to our data. Variant chr12-101757335-A-G is described in ClinVar as [Benign]. Clinvar id is 261695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101757335-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNPTAB	NM_024312.5	c.3336-25T>C		intron_variant		ENST00000299314.12	NP_077288.2
GNPTAB	XM_011538731.3	c.3255-25T>C		intron_variant			XP_011537033.1
GNPTAB	XM_006719593.4	c.3336-25T>C		intron_variant			XP_006719656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPTAB	ENST00000299314.12	c.3336-25T>C		intron_variant		1	NM_024312.5	ENSP00000299314.7
GNPTAB	ENST00000550718.1	c.147-25T>C		intron_variant		3		ENSP00000449557.1
GNPTAB	ENST00000549194.1	n.202-25T>C		intron_variant		3
GNPTAB	ENST00000549738.5	n.87-25T>C		intron_variant		4		ENSP00000450161.1

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46867 AN: 151780 Hom.: 7344 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.297

GnomAD3 exomes AF: 0.320 AC: 76594 AN: 239228 Hom.: 12522 AF XY: 0.316 AC XY: 40858 AN XY: 129212

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.395

Gnomad SAS exome AF: 0.241

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.319

GnomAD4 exome AF: 0.303 AC: 348234 AN: 1147900 Hom.: 53853 Cov.: 15 AF XY: 0.301 AC XY: 176372 AN XY: 584998

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.337

Gnomad4 ASJ exome AF: 0.327

Gnomad4 EAS exome AF: 0.374

Gnomad4 SAS exome AF: 0.238

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.297

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.309 AC: 46907 AN: 151902 Hom.: 7344 Cov.: 32 AF XY: 0.312 AC XY: 23178 AN XY: 74254

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.308

Gnomad4 ASJ AF: 0.317

Gnomad4 EAS AF: 0.393

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.443

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.296

Alfa AF: 0.303 Hom.: 1830

Bravo AF: 0.298

Asia WGS AF: 0.335 AC: 1162 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pseudo-Hurler polydystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Mucolipidosis type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3736476; hg19: chr12-102151113; COSMIC: COSV73418404;